Cerebrolysin: The basics

Introduction

EVER Neuro Pharma is an international pharmaceutical company engaged in the development, production and marketing of medications for treating neurodegenerative and cerebrovascular disorders.

The leading product of the company is Cerebrolysin – a worldwide recognised treatment of blood stroke, dementia and craniocerebral trauma and is marketed in more than 50 countries around the world.

Cerebrolysin history

The history of Cerebrolysin begins with the discovery of an Austrian professor Gerhart Harrer who, working at the University of Innsbruck, discovered that substances formed during the enzymatic hydrolysis of brain tissue may have a stimulating effect on nerve cells and correct vegetative disorders. After the process development of the medicinal product,

Cerebrolysin was first registered in Austria on August 1, 1954. First publications on the clinical use of brain hydrolysates in treating narcolepsy and hyperglycemic coma appeared during 1954-1956.

In 1975, the bioavailability studies of these hydrolysates and the first large-scale clinical trials of Cerebrolysin were conducted, during which its neuroprotective properties were proved.

In 1990, due to clinical trials in Austria, Germany, Japan and Russia, the neurotrophic effect of Cerebrolysin, its effectiveness in ischemic and degenerative brain diseases were proved.

The years of 1995-2005 were marked by a new breakthrough in studying the molecular modes of Cerebrolysin action. The randomised placebo-controlled trials justified the expansion of the range of clinical use of this medication.

The technology of Cerebrolysin production has fundamentally changed since 1980.

More sensitive methods (filtering by molecular weight, new methods for controlling the safety of raw materials, quantitative analysis) have been applied providing an increased degree of purification and improved quality control of the medication.

Cerebrolysin today is a high-tech medication produced with the help of the most modern and advanced technologies, while observing all the necessary standards used in pharmaceutical production. All sites manufacturing the substance and Cerebrolysin medication have GMP (Good Manufacturing Practice) certificates issued by the competent authorities of Austria and the European Union.

About Cerebrolysin

Cerebrolysin is well known to a wide range of clinicians, primarily to neurologists and psychiatrists. It is a peptidergic medication derived from porcine brain proteins during a standardised biotechnological manufacturing process. It contains biologically active peptides having neurotrophic and neuroprotective effects that mimic the effect of natural growth factors.

Thus, Cerebrolysin supports optimal functioning of neurons and improves their survival, has a positive effect on brain metabolism, stimulates neuronal and synaptic plasticity, protects against phenomena of excitotoxicity and oxidative stress. These molecular and cellular effects have a positive influence on the functioning of neurons, the overall level of CNS activity and mental performance of patients.

The proteolytic fraction of brain peptides stimulates cell differentiation, neuronal activity, induces mechanisms of defense and recovery. Cerebrolsyin is used to treat the following:

Cerebrolysin is a standardised preparation having a constant qualitative and quantitative composition. This means that, despite the complexity and multicomponent composition, the content of basic substances in Cerebrolysin is standardised, not only qualitatively, but also quantitatively.

1 ml of the drug solution contains 215.2 mg of Cerebrolysin concentrate, the active fraction of the preparation is represented by peptides, the molecular weight of which does not exceed 10,000 Daltons.

pH

6.5-7.5

Density

1.005-1.020

g/cm³

Protein

None

Dry residue

Not less than 40.00

mg/ml

Total nitrogen content

5.0-6.5

mg/ml

Peptide content (computational method)

25.0-30.0

%

Amino acid content

L-aspartic acid

2.40-3.60

mg/ml

L-glutamine acid

3.20-4.80

mg/ml

L-serine

0.21-0.39

mg/ml

L-histidine

1.04-1.56

mg/ml

Glycine

1.20-1.80

mg/ml

L-threonine

0.21-0.39

mg/ml

L-alanine

2.40-3.60

mg/ml

L-arginine

0.30-1.10

mg/ml

L-valine

1.60-2.40

mg/ml

L-methionine

0.35-0.65

mg/ml

L-tryptophan

0,35-0,65

mg/ml

L-isoleucine

1,60-2,40

mg/ml

L-phenylalanine

1,60-2,40

mg/ml

L-leucine

4,80-7,20

mg/ml

L-lysine

4,80-7,20

mg/ml

L-proline

1,60-2,40

mg/ml

Total amino acid content

28.08-42.12

mg/ml

Dosage and treatment courses

INDICATIONS FOR USE OF CEREBROLIZIN®

DOSAGE

TREATMENT COURSE

MODE OF ADMINISTRATION

Acute phase of ischemic stroke

30 мл

10 days

IVFD (intravenous fluid drip)

Recovery period of ischemic stroke

5-10 мл

10-20 days

intravenous or IVFD

Chronic cerebrovascular insufficiency

5-10 ml

10-15 days

intravenous or IVFD

Vascular dementia

20 ml

10-15 days

IVFD

Alzheimer’s disease

20 ml

10-15 days

IVFD

Complex therapy of depression

10-20 ml

10 days

IVFD

Psychoorganic syndrome

10 ml

10 days

intravenous or IVFD

Traumatic brain and spinal cord injuries

5-30 ml

10-15 days (different degrees of severity)

see table values

Mental retardation in children

0.1-0.2 ml/kg

20 days

intramuscular or intravenous or IVFD

Hyperactivity and attention deficit disorder in children

0.1 ml/kg

30 days

intramuscular or intravenous or IVFD

Cerebrolysin should be taken once a day. The course of treatment should be repeated 2-3 times a year.

Modes of administration

intramuscular

intravenous

IVFD

≤ 5 ml

+

+

+

10 ml

–

+

+

> 10 ml

–

–

+

Evidence of the mechanism of action

Physiological equivalence of Cerebrolysin and NTF

The effectiveness of Cerebrolysin arises from the fact that its neuropeptides act similarly to natural NTF. Using special laboratory methods, it was demonstrated that Cerebrolysin contains neuropeptides similar or identical to fragments of endogenous NTF (CNTF, GDNF, IGF-1, IGF-2).

Moreover, it has been shown that the optimal concentrations of each individual factor, especially CNTF, as well as of Cerebrolysin itself, counteract the negative effect of high concentrations of fibroblast (Growth Factor [FGF-2]) on neurogenesis and maturation of neurons that are observed in progenitor cells culture of the adult rat hippocampus. Since the regulation of neurogenesis, neuronal plasticity and neuronal maturation is one of the well established and proven physiological functions of NTF, the data obtained directly confirm the neurotrophic character of Cerebrolysin.

Calpains are the key enzymes involved in the process of apoptosis. The increased activity of calpains plays a role in a number of pathological processes related to a violation of calcium homeostasis – for example, Alzheimer’s disease, secondary degeneration of neurons after acute cellular damage (brain ischemia, traumatic brain injury, spinal cord injury).

Hyperactivated calpains destroy cytoskeleton proteins, such as spectrin, microtubule subunits, microtubule-associated proteins and neurofilaments. They can also damage ion channels, other enzymes, cell adhesion molecules and membrane receptors. This may lead to the destruction of the cytoskeleton and plasma membrane.

Various in vitro tests showed that Cerebrolysin reduces calpain activity by 60%. This result points out the potential role that Cerebrolysin therapy can play in reducing neural tissue damage in patients with neurological diseases.

DNA fragmentation occurs in the late stages of the apoptotic cascade, which is also evidence of neuronal degeneration. Cerebrolysin significantly reduces the number of apoptotic nuclei in the model of Alzheimer’s disease in transgenic animals (BPA-transgenic mice). Due to anti-apoptotic activity, Cerebrolysin increases the survival of neurons in both acute and chronic degenerative processes.

Free radicals play an important role in many biological processes, some of which are vital – for example, the destruction of bacteria by neutrophils or the transmission of a number of cellular signals.

However, free radicals are also involved in many pathological processes, such as Parkinson’s disease, senile or drug-induced deafness, schizophrenia, Alzheimer’s disease and ischemic cascades triggered by traumatic or non-traumatic brain injuries. Therefore, a decrease in the concentration of free radicals in the affected neural tissue is an important neuroprotection strategy aimed at reducing the range of brain damage.

The works of Sugita Y, Kondo T Kanazawa A, Itou T, Mizuno Y (1993) showed that Cerebrolysin significantly reduces the production of free radicals in experimentally induced ischemia in the animal model in vivo. The concentration of free radicals – metabolites of salicylic acid – (2.3-dihydroxybenzoic acid and 2.5-dihydroxybenzoic acid) decreased in the cortex and in the hippocampus indicating a neuroprotective effect of Cerebrolysin in ischemia.

Neuroplasticity (also known as brain plasticity) is the structural and functional ability of the brain to adapt to training, damage and is manifested by increased synaptogenesis and the formation of new neuronal networks.

The unique consequence of neuroplasticity is that brain activity associated with the function involved can move to other zones. And this may occur as a result of the experience, and as a result of the brain recovery after damage. Therefore, neuroplasticity is a fundamental property that supports the scientific concept of the treatment of acquired brain damage. In rehabilitation programs, stimulation of neuroplasticity with the help of therapeutic programs can be supplemented by medication stimulation.

The right figure shows: Cerebrolysin stimulated neuronal sprouting and increased the viability of nerve cells in vitro

Cerebrolysin significantly increased the number of new synapses in various parts of the hippocampus in experimental models of Alzheimer’s disease (transgenic animals), where neuroplasticity disorder, ß-amyloid deposition and neurodegenerative changes are observed from an early age. This fact was confirmed by an improvement in the behavioral activity of animals treated with Cerebrolysin.

The right figure shows: the number of synaptic connections in the neural tissue is higher in the brains of animals receiving Cerebrolysin.

In adulthood, the formation of new neurons occurs predominantly in two brain regions: the subventricular zone lining the lateral ventricles of the brain, from where the newly formed neurons migrate to the olfactory bulb along the rostral pathway, and in the subgranular zone that is part of the dentate gyrus of the hippocampus. The rate of neurogenesis in the hippocampus depends on many factors; there is evidence suggesting that hippocampal neurogenesis is important for learning and memory processes. It has been shown that training and environmental enrichment contributes to the survival of new neurons and their successful integration into hippocampal structures.

On the other hand, pharmacological stimulation of neurogenesis is considered as a potential means of promoting brain recovery after trauma and / or limiting the adverse effects of neurodegenerative disorders.

The following scheme shows that the number of newly formed neurocytes in the dentate gyrus of laboratory mice after 1 month of treatment with Cerebrolysin is more than twice as large as in the control group.

The recovery of brain tissue after injury, both acute or chronic, depends on effective stimulation of neural regeneration processes. Cerebrolysin stimulates neuroplasticity and neurogenesis, thus contributing to the optimal recovery of brain functions.